Synthesis of the macrocyclic core of iriomoteolide-1a

Article abstract of DOI:10.1039/c0cc00915f

The fully functionalized macrocyclic core of the marine natural product iriomoteolide-1a has been successfully constructed in a convergent and enantioselective manner.

Full text of DOI:10.1039/c0cc00915f

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Synthesis of the macrocyclic core of iriomoteolide-1aw
Shuo Li,a Zheng Chen,a Zhengshuang Xu*ab and Tao Ye*ab
Received 13th April 2010, Accepted 10th May 2010
First published as an Advance Article on the web 1st June 2010
DOI: 10.1039/c0cc00915f
The fully functionalized macrocyclic core of the marine natural
product iriomoteolide-1a has been successfully constructed in a
convergent and enantioselective manner.
The synthesis of the sulfone-based fragment 2 commenced
from a,b-unsaturated ester 5, which is readily available in
three steps starting from 1,3-propanediol.5 Sharpless asymmetric
dihydroxylation6 of 5 followed by exposure of the resulting
diol to dimethoxypropane and p-TsOH provided acetonide 6
in 97% yield (Scheme 1). DIBAL-H reduction of the
methyl ester in 6 afforded the corresponding primary alcohol,
which allowed for conversion to the terminal alkene (7)
in 81% overall yield via Dess–Martin7 oxidation and sub-
sequent olefination with methylenetriphenylphsophorane.8
The p-methoxybenzyl group was removed from 7 with
DDQ, and the primary alcohol was converted into the corres-
ponding aldehyde by Dess–Martin oxidation.7 This material
was then homologated to methyl ketone 8 using a two-step
procedure including nucleophilic addition using MeMgBr and
Dess–Martin oxidation. Boron-mediated 1,5-anti aldol reaction9
was employed for the construction of b-hydroxy ketone 9.
Thus, the methyl ketone 8 was enolized using (c-Hex)2BCl and
Iriomoteolide-1a (Fig. 1) is a new member of a family of
structurally related cytotoxic natural products isolated from
strains of microscopic marine dinoflagellates.1 Its structure is
defined by a 20-membered macrolactone punctuated by nine
stereogenic centers, three endogenous double bonds, one
exo-methylene unit and one six-membered hemiketal ring.2
Relative and absolute stereochemistry assignments were based
on extensive NMR studies, including modified Mosher ester
analysis. Iriomoteolide-1a displayed potent cytotoxicity
against human B lymphocyte DG-75 cells (IC50: 0.002 mg mLÀ1
)
and Epstein–Barr virus (EBV)-infected human B lymphocyte
Raji cells (IC50: 0.003 mg mLÀ1).2 Owing to its interesting
structural features and biological properties, iriomoteolide-1a
has attracted the attention of synthetic chemists over the past
three years. To date no total synthesis of iriomoteolide-1a has
yet been reported. However, the preparation of fragments
corresponding to C1–C9,3a C1–C12,3b,c C13–C233a,d–f and
C7–C233g,h of iriomoteolide-1a has been disclosed. As part of
a program directed toward the synthesis, structural modifica-
tion, and biological evaluation of marine natural products,4
we have developed and report herein a convergent, highly
stereocontrolled approach to the macrocyclic core of iriomo-
teolide-1a.
Hunig’s base at À78 1C. Addition of aldehyde 11 at À78 1C
¨
then gave the desired 1,5-anti adduct 9 in 85% yield and with
no visible trace of the syn stereoisomer (dr > 50 : 1). Conversion
of 9 to diene 10 was achieved by a three-step sequence of
straightforward transformations: (i) oxidation of the PMB
ether to the corresponding PMP acetal,10 (ii) olefination with
methylenetriphenylphosphorane,8 and (iii) reductive opening
of the PMP acetal with Dibal-H.11 Mitsunobu reaction12
of alcohol 10 with 1-phenyl-1H-tetrazole-5-thiol (PTSH)
followed by oxidation with hydrogen peroxide and ammonium
heptamolybdate tetrahydrate13 furnished sulfone 2 in 97%
yield (two steps).
As outlined in our retrosynthetic analysis, iriomoteolide-1a
could be simplified by utilizing macrolactone 1 as the advanced
precursor with the six-membered hemiketal ring being
installed at a later stage in the total synthesis. It was envisaged
that the 20-membered macrolactone 1 could be constructed by
ruthenium-catalyzed ring closing metathesis (RCM) of the
corresponding precursor which was planned to be assembled
from three fragments of comparable complexity (Fig. 1).
This strategy would confine protecting group operations and
oxidation state adjustments to a minimum.
The synthesis of fragment 3 started with the protection of
the known chiral ester 1214 as its TBDPS ether, followed by
DIBAL-H reduction of the methyl ester to afford alcohol 13
in 94% yield (Scheme 2). Oxidation with the Dess–Martin
periodinane7 and
a
subsequent Corey–Fuchs reaction15
a Laboratory of Chemical Genomics, Peking University Shenzhen
Graduate School, University Town of Shenzhen, Xili,
Nanshan District, Shenzhen, China 518055.
E-mail: yet@szpku.edu.cn, xuzs@szpku.edu.cn
b Department of Applied Biology & Chemical Technology,
The Hong Kong Polytechnic University,
Hung Hom, Kowloon, Hong Kong, China.
E-mail: bctaoye@inet.polyu.edu.hk; Tel: +852 34008722
w Electronic supplementary information (ESI) available: Full details
for experimental procedures for compounds 1–5, 5a, 6, 6a, 6b, 7, 7a,
7b, 8–9, 9a, 9b, 10, 10a, 12a, 13, 13a, 14–15, 15a, 15b, 17–19, 19a, 20,
20a, 21, 21a, 21b and 22 and 1H and 13C NMR spectra for compounds
1–5, 5a, 6–7, 7a, 8-9, 9a, 9b, 10, 10a, 12a, 13, 14–15, 15a, 19, 19a, 20,
20a, 21, 21a, and 22. See DOI: 10.1039/c0cc00915f
Fig. 1 Structure and retro-synthetic analysis of iriomoteolide-1a.
Chem. Commun., 2010, 46, 4773–4775 | 4773
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Scheme 3 (a) TBDPSCl, imidazole, DMAP, DMF; (b) OsO4, NaIO4,
2,6-lutidine; (c) MeOCHQPPh3, THF; (d) 5 N HCl, CH2Cl2–THF; (e)
KOBut, trans-2-butene, n-BuLi, (À)-IPC2BOMe, then BF3ÁOEt2, 18,
À78 1C; 3 N NaOH, 30% H2O2; dr > 97 : 3; (f) TESOTf, 2,6-lutidine,
CH2Cl2; (g) 9-BBN, 3 N NaOH, 30% H2O2; (h) Dess–Martin
periodinane, NaHCO3, CH2Cl2; (i) CH2QPPh3, THF; (j) 3 N HCl,
CH2Cl2–THF.
Scheme 1 (a) K3Fe(CN)6, AD-mix-b, MeSO2NH2; (b) 2,2-dimethoxy-
propane, TsOH; (c) DIBAL-H, THF; (d) Dess–Martin periodinane,
NaHCO3, CH2Cl2; (e) CH2QPPh3, THF; (f) DDQ, CH2Cl2–H2O; (g)
Dess–Martin periodinane, NaHCO3, CH2Cl2; (h) CH3MgI, Et2O; (i)
Dess–Martin periodinane, CH2Cl2; (j) c-Hex2BCl, DIPEA then 11,
dr > 50 : 1; (k) DDQ, CH2Cl2; (l) CH2QPPh3, THF; (m) DIBAL-H,
CH2Cl2; (n) PTSH, DIAD, PPh3; (o) (NH4)6Mo7O24Á4H2O, NaOAc,
50% H2O2/EtOH.
diastereomeric ratio higher than 97 : 3. Protection of the
secondary alcohol in 19 as its triethylsilyl ether, followed by
alkene hydroboration/oxidation21 with 9-borabicyclo[3.3.1]-
nonane (9-BBN) and alkaline hydrogen peroxide furnished
the corresponding alcohol 20 in 86% yield (over two steps).
Dess–Martin oxidation of the primary alcohol in 20 to the
corresponding aldehyde which was subjected to a Wittig
olefination followed by removal of the TES-ether then
completed the fragment 4 in 86% yield (over three steps).
With the three target fragments in hand, the stage was now
set for their assembly and elaboration into macrocycle 1
(Scheme 4). Our fragment assembly began with coupling of
fragments 3 and 4. Thus, the esterification of alcohol 4
with carboxylic acid 3 was carried out under Yamaguchi
conditions22 to yield the corresponding ester which was then
treated with pyridinium p-toluenesulfonate (PPTS) in
EtOH–H2O to afford alcohol 21 in 80% yield (over two steps).
For the completion of the construction of RCM precursor 22,
alcohol 21 and sulfone 2 were connected by using an
E-selective one-step Kocienski–Julia olefination.23 Thus,
Dess–Martin oxidation of 21 provided the corresponding
crude aldehyde, which was treated with the anion derived
from sulfone 2 and LiHMDS in DMF/HMPA at À50 1C, to
provide alkene 22 with excellent E-selectivity (E : Z > 10 : 1) in
75% yield. With tetraene 22 in hand, we proceeded to study
the key RCM step for the formation of the 20-membered ring.
Gratifyingly, exposure of 22 to Hoveyda–Grubbs’ second-
generation catalyst24 in refluxing toluene delivered the desired
macrocycle 1 as the only isolable product in 51% yield.
In summary, the carbocyclic skeleton of the marine natural
product iriomoteolide-1a has been prepared via a convergent
route that employed boron-mediated 1,5-anti aldol reaction,
Yamaguchi esterification, Kocienski–Julia olefination and
ring-closing metathesis as the key steps. The elaboration of
macrolactone 1 to natural iriomoteolide-1a is ongoing in
our laboratories and will be reported in due course. After
acceptance of this manuscript for publication, Horne and
coworkers reported a total synthesis of proposed structure of
iriomoteolide-1a.25
in which the anion was trapped with ethyl chloroformate
established the acetylenic compound 14 in 74% yield over
three steps. 1,4-Addition of Gilman’s reagent to ester 14
furnished the alkene ester 15 in 94% yield.16 To our surprise,
attempts to hydrolyze ester 15 were unsuccessful. This ester
was then converted into the corresponding acid 3 by the use of
a three-step process involving DIBAL-H reduction of the ester
to an allylic alcohol that was then subjected to sequential
manganese dioxide and Pinnick17 oxidations to afford the
corresponding carboxylic acid 3.
The preparation of the C16–C23 fragment 4 began with the
protection of the known homoallylic alcohol 1618 as its
TBDPS ether, followed by oxidative cleavage of the terminal
alkene19 to afford the corresponding aldehyde 17 in 88% yield
over two steps (Scheme 3). Aldehyde 17 was then subjected to
a Wittig olefination/acidic hydrolysis sequence,20 which led to
homologated aldehyde 18 in 83% yield. Aldehyde 18 was then
reacted with Brown’s (E)-crotyldiisopinocampheylborane
prepared from (À)-diisopinocampheyl(methoxy)borane, and
yielded the anti-homoallylic alcohol 19 in 78% yield,18 with a
Scheme 2 (a) TBDPSCl, imidazole, DMAP, DMF; (b) DIBAL-H,
THF, À78 to 0 1C; (c) Dess–Martin periodinane; (d) CBr4, PPh3,
CH2Cl2; (e) n-BuLi, ClCO2Et, THF; (f) MeLi, CuI, THF; (g)
DIBAL-H, THF, À78 to 0 1C; (h) MnO2, CH2Cl2; (i) NaClO2,
NaH2PO4, t-BuOH–H2O.
We acknowledge financial support from the Hong Kong
Research Grants Council (Projects: PolyU5407/06M
&
PolyU5638/07M) and financial support from the Shenzhen
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